1. Field of Invention
This invention relates to therapeutic compositions in unit dosage form which are capable of floating on gastric fluid and delivering their contained therapeutic agent over an extended period of time.
2. Description of the Prior Art
The convenience of administering a single dose of a medication which releases active ingredients over an extended period of time as opposed to the administration of a number of single doses at regular intervals has long been recognized in the pharmaceutical arts. The advantage to the patient and clinician in having consistent and uniform blood levels of medication over an extended period of time are likewise recognized.
The conventional approaches to sustained release can be disadvantageous when the medicament is administered orally because certain classes of active ingredients are not suited to absorption during passage through the gastrointestinal tract due to their physiochemical properties and/or favorable sites of absorption. Penicillin, for example, is fully absorbed at one point in the intestine. Once the dosage unit containing pencilllin passes this point under the influence of peristaltic movement, the remaining penicillin is not absorbed into the blood stream, but is excreted.
Most medicaments will undergo varying degrees of change in solubility by passage from the strongly acid conditions of the stomach to the neutral and to the alkaline conditions of the intestines. Additionally, there are medicaments, e.g. antacids which are intended to act in the stomach and therefore lose most beneficial properties when they pass into the intestine.
The advantages of sustained release dosage forms, which are retained in the stomach, for example, by floating in the gastric fluid, slowly releasing their therapeutic contents into the gastric fluid for passage through the intestinal tract, will be readily apparent. These include (1) increased contact time for local activity in the stomach, where such is required, as in the treatment of stomach ulcers, (2) increased and more efficient absorption for drugs which have specific absorption sites, and (3) the ability to reduce the number of dosages.
A number of patents disclose therapeutic dosage forms which float on the gastric fluid and have sustained release capabilities. In a series of U.S. Patents: (U.S. Pat. Nos. 4,126,672; 4,140,755; 4,167,558), Sheth and Tossounian claim compressed tablets and capsules containing from about 20% to about 75% by weight of one or a mixture of hydrocolloids as carriers for therapeutic agents. The hydrocolloids recited in the examples and in the claims are cellulose derivatives including methylcellulose, hydroxyalkylcelluloses and carboxymethyl-cellulose. The products are said to be in hydrodynamic balance so that, upon contact with gastric fluid, the hydrocolloids hydrate and acquire a bulk density of less than one, thereby being buoyant in the gastric fluid. The presence of pharmaceutically inert fatty materials having a specific gravity of less than one decreases the hydrophilicity and increases the buoyancy of the dosage form.
Urquahart and Theeuwes in U.S. Pat. No. 4,434,153 describes a prolonged release system in which coated tiny pills comprising a wall of "drug release rate controlling" wax surrounding a core of medicament, are dispersed in a hydrophilic matrix and compressed to a tablet in which the matrix swells in stomach fluid for extended residency therein.
Mitra in U.S. Pat. No. 4,451,260 described a sustained release device which is a multilayer composite comprising a carrier film which is water-insoluble and contains a medicament and a barrier film comprising a water-insoluble, water- and medicament-permeable polymer. The two films are sealed in such a way as to entrap a plurality of small pockets of air between said films. The air-containing composite has a bulk density of less than one so as to render it buoyant in gastric fluid. The composite film is cut into desired lengths which are folded to fit inside a gelatin capsule. Upon oral administration, the capsule dissolves and the insoluble composite film floats on the gastric fluid.
Hydrophilic polymers or hydrocolloids have been used in sustained release dosage forms which have been prepared without compression.
The procedure disclosed by Nakano et al in J. Pharm. Pharmacol., 31, 869 (1979) and referred to in Chem. Pharm. Bull., 28, 2905 (1980), involves dissolving agar in water at 90.degree. C. and, after the solution is cooled to 70.degree. C., sulphamethizole is suspended in the agar solution. The drug suspension, containing about 6% agar and 8% drug is then extruded through a plastic syringe onto the top of a cold water-immiscible organic solvent such as ethyl acetate, to form drug-containing beads which are separated from the solvent by filtration and dried. The dried beads contain about 40% agar. There is no indication of the density of the beads or whether they can float on gastric fluid.
A procedure disclosed by Nakano et al in Chem. Pharm. Bull., 27, 2834 (1979) involves swelling konjac flour with water and extruding the resulting sol, containing 5% konjac, from a plastic syringe into boiling water saturated with calcium hydroxide. After a period of boiling, an elastic gel is obtained and is washed with water to remove the alkali. The gel is then placed at 70.degree. C. into an ammoniacal solution containing 5% theophylline to permit the drug to permeate into the gel. The gel containing theophylline is then dried to constant weight and cut into pieces. The dried gel contains 55% konjac. There is no indication of the density of the dried gel or whether the pieces can float on gastric fluid.
Boraie and Naggar in Acta Pharm. Jugosl., 34, 247 (1984) disclose a procedure for preparing non-compressed tablets which involves preparing an aqueous suspension containing at least 7.5% agar and a medicament such as theophylline, at an agar/drug ratio of 1/0.5 to 1/1.33, and charging said suspension into a tablet mold and cooling. The molded tablets are removed from the mold and dried. The dried tablets have an agar content of at least 43%. There is no indication of the density of the dried tablets or whether they will float on gastric fluid.
It is noteworthy that, although Sheth and Tossounian (op cit) disclose the preparation of compressed tablets and capsules which float on gastric fluid, they specifically caution against the use of water or other solvent for the hydrocolloid. "In the practice of the invention, the hydrocolloid is incorporated into the formulation in dry form . . . Wherein a hydrocolloid such as described herein is combined in the formulation in the presence of a solvent, such hydrocolloid does not function to facilitate the buoyancy of the tablets prepared therefrom" (U.S. Pat. No. 4,167,558, col. 5, lines 37-53).
Our co-pending U.S. application Ser. No. 722,832 filed Apr. 12, 1985, discloses non-compressed therapeutic compositions containing 0.5 to 4% gelling agent, 10 to 20% therapeutically acceptable inert oil and 50 to 75% therapeutic agent and capable of floating on gastric fluid and delivering their contained therapeutic agent over an extended period of time.
The present invention is directed toward an oil-free, non-compressed therapeutic composition in unit dosage form, having a low concentration of gelling agent and at least 75% therapeutic agent and capable of floating on gastric fluid, and providing sustained release of the therapeutic agent upon administration.